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Familial Mediterranean Fever and Related Disorders: Genetics and Disease Characteristics

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ClinicalTrials.gov Identifier: NCT00001373
Recruitment Status : Recruiting
First Posted : November 4, 1999
Last Update Posted : October 27, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:

This study is designed to explore the genetics and pathophysiology of diseases presenting with intermittent fever, including familial Mediterranean fever, TRAPS, hyper-IgD syndrome, and related diseases.

The following individuals may be eligible for this study: 1) patients with known or suspected familial Mediterranean fever, TRAPS, hyper-IgD syndrome or related disorders; 2) relatives of these patients; 3) healthy, normal volunteers 7 years of age or older.

Patients will undergo a medical and family history, physical examination, blood and urine tests. Additional tests and procedures may include the following:

  1. X-rays
  2. Consultations with specialists
  3. DNA sample collection (blood or saliva sample) for genetic studies. These might include studies of specific genes, or more complete sequencing of the genome.
  4. Additional blood samples a maximum of 1 pint (450 ml) during a 6-week period for studies of white cell adhesion (stickiness)
  5. Leukapheresis for collecting larger amounts of white cells for study. For this procedure, whole blood is collected through a needle in an arm vein. The blood flows through a machine that separates it into its components. The white cells are removed and the rest of the blood is returned to the body through another needle in the other arm.

Patients may be followed approximately every 6 months to monitor symptoms, adjust medicine dosages, and undergo routine blood and urine tests. They will receive genetic counseling by the study team on the risk of having affected children and be advised of treatment options.

Participating relatives will undergo a medical and family history, possibly with a review of medical records, physical examination, blood and urine tests. Additional procedures may include a 24-hour urine collection, X-rays, and consultations with medical specialists. A DNA sample (blood or saliva) will also be collected for genetic studies. Additional blood samples of no more than 550 mL during an 8-week period may be requested for studies of white cell adhesion (stickiness).

Relatives who have familial Mediterranean fever, TRAPS, or hyper-IgD syndrome will receive the same follow-up and counseling as described for patients above.

Normal volunteers and patients with gout will have a brief health interview and check of vital signs (blood pressure and pulse) and will provide a blood sample (up to 90 ml, or 6 tablespoons). Additional blood samples of no more than 1 pint over a 6-week period may be requested in the future.

Condition or disease
Familial Mediterranean Fever (FMF)

Detailed Description:

The purpose of this protocol is to study the genetics and pathophysiology of familial Mediterranean fever (FMF) and other related diseases. FMF is a recessively inherited condition characterized by episodes of fever and serositis or synovitis; some patients also develop systemic amyloidosis. Our laboratory has identified the FMF gene and several disease-related mutations. The FMF gene encodes a protein called pyrin that is the prototype of a family of molecules involved in the regulation of apoptosis (cell-death) and inflammation. The precise biochemical mechanism by which these proteins function, and by which mutations cause disease, is still unknown.

There are a number of other conditions, sometimes referred to as autoinflammatory syndromes because of the lack of high-titer autoantibodies or antigen-specific T-cells that are also characterized by episodic inflammation. Seven are caused by mutations in five other genes: the TNF-receptor associated periodic syndrome (TRAPS) is caused by mutations in one of the receptors for tumor necrosis factor (TNF); the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) is caused by mutations in the gene encoding mevalonate kinase; Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID) are caused by mutations in the gene encoding cryopyrin, a member of the aforementioned pyrin family of proteins; deficiency of the interleukin-1 receptor antagonist (DIRA) is caused by mutations in the gene that codes for the interleukin-1 receptor antagonist, a protein that helps to regulate levels of the inflammatory cytokine, interleukin-1; and the syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) is caused by mutations in PSTPIP1, a protein that binds pyrin. In addition, there are patients with episodic fevers and/or inflammation who do not have identifiable mutations in any of these genes. Some of these latter cases appear to cluster in families, while others are sporadic.

The goals of this protocol are: 1) to gather and evaluate clinical data on selected patients with FMF and related conditions, so as to characterize more thoroughly the clinical features and natural history of patients with recognized disorders as well as those with as yet undefined autoinflammatory conditions; 2) to identify mutations, both in known autoinflammatory genes and in other genes, that lead to syndromes of periodic inflammation, and to study possible correlations between specific genetic mutations and disease manifestations; and 3) to undertake functional, biochemical, and molecular studies of leukocytes from patients with both known and as yet poorly defined autoinflammatory conditions.

Patients will undergo screening history, physical examination, and clinical laboratory evaluation, usually in the outpatient department. Imaging studies and other procedures may be performed when clinically indicated. Where appropriate, we will ask probands to obtain permission from family members to be contacted. We will collect blood samples from consenting affected individuals and, in some cases, unaffected family members, extract DNA, and perform molecular genetic analyses. For cellular and biochemical studies, we will obtain blood samples and possibly salivary samples from patients, selected unaffected family members, and unrelated controls. In some cases adult patients may be asked to interrupt treatment temporarily to obtain additional blood samples.

Study Design

Study Type : Observational
Estimated Enrollment : 199998 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Genetics and Pathophysiology of Autoinflammatory Disorders.
Study Start Date : March 10, 1994

Groups and Cohorts

Outcome Measures

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

    1. Individuals referred to the NIH with a possible diagnosis of FMF, TRAPS, HIDS, MWS, FCAS, NOMID, DIRA, PAPA, PFAPA, or other unexplained febrile or inflammatory illnesses. Individuals may be seen for initial evaluation, genetic studies, and research blood specimens, or may send blood or saliva samples for genetic testing only. However, we place the following age restrictions on other studies:

      1. Leukapheresis will only be performed on individuals over the age of 18 years;
      2. Brief interruption of ongoing therapy for research blood sampling will only be proposed to individuals over the age of 18 years;
    2. Family members of individuals included under item 1: may be seen for initial evaluations, genetic studies, or research blood specimens, or may send blood or buccal samples for genetic testing only. Unaffected family members will not be asked to undergo leukapheresis or, interruption of ongoing therapy.
    3. Controls for cellular, molecular, biochemical assays and genetic studies: Individuals who undergo phlebotomy specifically to provide a random control specimen will be required to be over the age of 7 years and not pregnant. Individuals providing a control specimen who are already undergoing phlebotomy for other reasons must be greater than 1 year of age and not pregnant.


  1. In the case of adults, inability to provide informed consent and unavailability of a legally authorized representative (LAR) to provide surrogate consent.
  2. In the case of minors, unavailability of a parent or guardian.
  3. Presence of any medical condition that would, in the opinion of the investigators, confuse the interpretation of the study.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00001373

Contact: Amanda K Ombrello, M.D. (301) 827-4258 ombrelloak@mail.nih.gov
Contact: Daniel L Kastner, M.D. (301) 402-2023 kastnerd@mail.nih.gov

United States, District of Columbia
Childrens National Medical Center Recruiting
Washington, D.C., District of Columbia, United States
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21205
Walter Reed National Medical Center Recruiting
Bethesda, Maryland, United States, 20301
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
National Human Genome Research Institute (NHGRI)
University of Massachusetts, Worcester
Duke University
Merck Sharp & Dohme Corp.
Principal Investigator: Daniel L Kastner, M.D. National Human Genome Research Institute (NHGRI)
More Information

Additional Information:
Responsible Party: National Human Genome Research Institute (NHGRI)
ClinicalTrials.gov Identifier: NCT00001373     History of Changes
Other Study ID Numbers: 940105
First Posted: November 4, 1999    Key Record Dates
Last Update Posted: October 27, 2017
Last Verified: October 17, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) ):
Familial Mediterranean Fever
Periodic Fever

Additional relevant MeSH terms:
Hereditary Autoinflammatory Diseases
Familial Mediterranean Fever
Body Temperature Changes
Signs and Symptoms
Gram-Negative Bacterial Infections
Bacterial Infections
Genetic Diseases, Inborn
Skin Diseases, Genetic
Skin Diseases